Vogelstein 20/20 Ratiometric Driver Discovery

Overview

The Vogelstein 20/20 ratiometric scheme is a rule-based statistical method for classifying cancer driver genes as oncogenes or tumor suppressors, originally described in Vogelstein et al. (2013, Science). A gene is classified as a driver if it exceeds a minimum recurrence threshold (≥5 recurrent or inactivating mutations) and meets either the oncogene criterion (≥20% of mutations are recurrent missense at known hotspots, ONC ≥ 20%) or the tumor-suppressor criterion (≥20% of mutations are inactivating with oncogenic fraction ≤5%, TSG ≥ 20%, ONC ≤ 5%). The method is applied per cancer type or molecular subtype (e.g., ER+ vs ER-) and can identify both oncogenes (enriched for recurrent gain-of-function missense mutations) and tumor suppressors (enriched for loss-of-function events).

Used by

Notes

  • The 20/20 rule is intentionally conservative; it requires strong enrichment of a single mutation class and thus may miss genes with mixed mutation patterns.
  • ER-stratification (applied in the METABRIC study) increases sensitivity for subtype-restricted drivers that would be diluted in an unstratified analysis.
  • Minimum recurrence threshold of ≥5 mutations limits detection in small cohorts; the METABRIC n=2,433 was specifically assembled to overcome this.
  • The method does not use statistical background mutation rate modeling (unlike MutSig); it relies on mutation-type composition ratios.

Sources

  • Vogelstein B et al. (2013) Cancer genome landscapes. Science 339:1546–1558.
  • PMID:27161491

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